Subsets of human natural killer cells and their regulatory effects

Abstract

Human natural killer (NK) cells have distinct functions as NK(tolerant) , NK(cytotoxic) and NK(regulatory) cells and can be divided into different subsets based on the relative expression of the surface markers CD27 and CD11b. CD27⁺ NK cells, which are abundant cytokine producers, are numerically in the minority in human peripheral blood but constitute the large population of NK cells in cord blood, spleen, tonsil and decidua tissues. Recent data suggest that these NK cells may have immunoregulatory properties under certain conditions. In this review, we will focus on these new NK cell subsets and discuss how regulatory NK cells may serve as rheostats or sentinels in controlling inflammation and maintaining immune homeostasis in various organs.

Keywords: cell differentiation; human natural killer cells.

Figure 1

Four natural killer (NK) subsets defined by CD11b and CD27 in humans. Human NK cells can be divided into four subsets on the basis of the relative expressions of the markers CD11b and CD27, including CD11b⁺ CD27⁻ (CD11b⁺ SP), CD11b⁺ CD27⁺ (DP), CD11b⁻ CD27⁺ (CD27⁺ SP) and CD11b⁻ CD27⁻ (DN). More than 90% of NK cells from peripheral blood (pNK) are of the CD11b⁺ CD27⁻ population, whereas NK cells from cord blood (cNK) have 80% CD11b⁺ CD27⁻ and 20% CD11b⁺ CD27⁺ subset. Decidual NK cells (dNK) are nearly 60% CD11b⁻ CD27⁻ and > 20% CD27⁺ subset. NK cells from tumour-infiltrating tissues (TINK) also show a large population of the CD11b⁻CD27⁻ subset.

Figure 2

Human natural killer (NK) subsets presented according to phenotype and function. Human NK cells can be divided into three functional subsets: NK^tolerant, which is mainly CD56^bright NK cells or CD27⁻ CD11b⁻ NK cells; NK^cytotoxic, which is mainly CD56^dim NK cells or CD11b⁺ CD27⁻ NK cells; NK^regulatory, which is mainly CD56^bright NK cells or CD27⁺ NK cells.

Figure 3

The programmed differentiation of natural killer (NK) cells and the generation of NK^tolerant, NK^cytotoxic and NK^regulatory cells. The programmed differentiation of NK cells can be divided into three steps. First, NK cells predominantly develop from CD34⁺ haematopoietic stem cells (HSCs) in the physiological microenvironment of bone marrow or lymph nodes, producing immature NK (iNK) cells. Second, under the effect of chemokines, NK cells are recruited into different pathological microenvironments, such as the uterus and brain, and then develop under the control of specific cytokines and transcription factors. Third, these differentiated NK cells may act as NK^tolerant, NK^cytotoxic or NK^regulatory cells. IFN-γ, interferon-γ; IGF-1, insulin-like growth factor 1; IL-7, interleukin-7; SCF, stem cell factor; STAT3, signal transducer and activator of transcription 3; TGF-β, transforming growth factor-β. ??? refers to unknown transcription factors that provide important intrinsic signals to impact the differentiation of regulatory NK cells.

Figure 4

Key pathways of the regulatory decidual natural killer (dNK) cells involved in immune tolerance during the first trimester of human pregnancy. Decidual NK cells with a CD56^bright CD16⁻ phenotype can control trophoblast invasion and vascular remodelling, inhibit inflammatory T helper type 17 cells, promote the generation of indoleamine 2,3-dioxygenase (IDO)-producing monocytes and regulatory T cells and induce the apoptosis of effector T cells. Meanwhile, dNK cells are maintained and educated by the decidual microenvironment including stromal cells, trophoblast cells and hormones such as progesterone. IFN-γ, interferon-γ; IL, interleukin; MIC-1, macrophage inhibitory cytokine-1; MIP-1α, macrophage inflammatory protein-1α; PlGF, placental growth factor; SCDF-1, stromal cell-derived factor-1; SCF, stem cell factor; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor.